Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy

Brodie, Martin J.; Lerche, Holger; Gil‐Nagel, Antonio; Elger, Christian E.; Hall, Susan T.; Shin, Paul; Nohria, Virinder; Mansbach, Hank

doi:10.1212/wnl.0b013e3181fd6170

Cited by 176 publications

(210 citation statements)

References 36 publications

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“…Seizure-free rates counted from the time of randomization were low, as expected in a refractory population: 3.2% at 600 mg/day and 4.7% at 900 mg/day, not statistically different from the 1.2% placebo rate (17).…”

Section: Efficacysupporting

confidence: 50%

“…In clinical trials, there were single reported cases of suicidal ideation and of psychosis (16). Sudden death rates did not exceed reported rates for individuals with refractory epilepsy (16,17,18).…”

Section: Safetymentioning

confidence: 85%

“…Adverse effects with a definite dose-relationship were dizziness and somnolence (17). The dizziness was not usually associated with ataxia.…”

Section: Tolerabilitymentioning

confidence: 98%

“…Concerns about possible cardiac effects of potassium-channel actions have been allayed by the normal results of ECGs in human trials, including a 24-hour Holter monitor in the first trial (16). In contrast to some other antiepileptic drugs, EZG-treated subjects were virtually rash-free (16,17,18), had no visual field effects with formal testing (16), and had no clinically significant changes in hepatic enzymes or hematological parameters (16,17,18). In clinical trials, there were single reported cases of suicidal ideation and of psychosis (16).…”

Section: Safetymentioning

confidence: 99%

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Ezogabine: A New Angle on Potassium Gates

Faught

2011

Epilepsy Curr

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Section: Efficacysupporting

confidence: 50%

Section: Safetymentioning

confidence: 85%

“…Adverse effects with a definite dose-relationship were dizziness and somnolence (17). The dizziness was not usually associated with ataxia.…”

Section: Tolerabilitymentioning

confidence: 98%

Section: Safetymentioning

confidence: 99%

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Ezogabine: A New Angle on Potassium Gates

Faught

2011

Epilepsy Curr

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“…Efficacy for this first-in-class agent was demonstrated in phase III clinical trials (23,24). Safety issues associated with ezogabine include dizziness, somnolence, confusion, and fatigue, which are all common for CNS-acting drugs.…”

Section: Improve Antiseizure Therapies That Target Novel or Multiple mentioning

confidence: 99%

2014 Epilepsy Benchmarks Area III: Improve Treatment Options for Controlling Seizures and Epilepsy-Related Conditions without Side Effects

Stewards

2016

Epilepsy Curr

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Epilepsy Resources and UpdatesThe Epilepsy Benchmark goals in Area III focus on making progress in understanding and controlling seizures and related conditions as well as on developing biomarkers and new therapies that will reduce seizures and improve outcomes for individuals with epilepsy. Area III emphasizes a need to better understand the ways in which seizures start, propagate, and terminate and whether those network processes are common or unique in different forms of epilepsy. The application of that knowledge to improved seizure prediction and detection will also play a role in improving patient outcomes. Animal models of treatment-resistant epilepsy that are aligned with etiologies and clinical features of human epilepsies are especially encouraged as necessary tools to understand mechanisms and test potential therapies. Antiseizure therapies that target (either alone or in combination) novel or multiple seizure mechanisms are prioritized in this section of the Benchmarks. Area III goals also highlight validation of biomarkers of treatment response and safety risk, effective self-management, and patient-centered outcome measures as important areas of emphasis for the next five to ten years. Key Advances in Area III Developing and Refining Animal ModelsAnimal models are needed to test interventions targeted to various features of epilepsy, such as delaying the latency between initial insult and onset of spontaneous seizures, preventing the progression of epilepsy severity over time, converting pharmacoresistant to anticonvulsant-responsive seizures, and alleviating behavioral comorbidities. Progress has been made to address some of these aspects of disease modification and to identify etiologically relevant epilepsy animal models. One etiologically relevant animal model of cerebral viral infection is that produced by inoculation of mice with Theiler murine encephalomyelitis virus, which produces a strong neuroinflammatory reaction coupled with seizures and the development of long-term cognitive deficits (1). A similar model of cerebral malaria produces epilepsy that appears dependent on an intact complement pathway (2).Posttraumatic epilepsy is a leading cause of epilepsy in young adults. Much effort has been devoted to developing etiologic animal models that lend themselves to drug screening and can be used to understand mechanisms of epileptogenesis in this condition. A recent study (3) reported the parametric optimization of a rat fluid percussion model that results in focal, nonconvulsive, brief seizures. In this model young (1 month old) male Sprague Dawley rats are subjected to an abrupt percussive injury to the parietal cortex. Within

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Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis

et al. 2021

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IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials. OBJECTIVE To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS. DESIGN, SETTING, AND PARTICIPANTSThis double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements. INTERVENTIONS Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks. MAIN OUTCOMES AND MEASURESThe primary outcome was change in short-interval intracortical inhibition (SICI; SICI −1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.RESULTS A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI −1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI −1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, −2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001).CONCLUSIONS AND RELEVANCE Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.

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Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy

Abstract: This study provides Class II evidence that adjunctive EZG/RTG reduces the occurrence of partial-onset seizures.

Cited by 176 publications

References 36 publications

Ezogabine: A New Angle on Potassium Gates

Ezogabine: A New Angle on Potassium Gates

2014 Epilepsy Benchmarks Area III: Improve Treatment Options for Controlling Seizures and Epilepsy-Related Conditions without Side Effects

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis

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